Antitumoral compounds

ABSTRACT

Azaanthracene-triones of the formula: ##STR1## (in which: R 1 , R 2 , R 4  and R 5  are the same or are different and each is a hydrogen atom or a lower alkyl group; 
     R 3  is a hydrogen atom, a lower alkyl group, a phenyl group or an amino-substituted phenyl group; and 
     X is a --CH--, ═N-- or --NH--, whereby the ring containing the group X is a benzene, pyridine or dihydropyridene ring) 
     have antitumoral activity.

This is a continuation of application Ser. No. 08/073,109 filed on Jun.4, 1993 now abandoned.

FIELD OF THE INVENTION

This invention relates to antitumoral compounds and to pharmaceuticalcompositions containing them.

BACKGROUND OF THE INVENTION

Diazaquinomicyn A is a natural 1,8-diazaanthraquinone found during theroutine study of secondary metabolites from bacteria. [S. Omura, et.al., J. Antibiotics, 35, 1425 (1982); and S. Omura et. al., TetrahedronLetters, 24, 3643 (1963)]. It exhibits good activity against Grampositive bacteria, due to its capacity to inhibit the thymidylatesynthetase [S. Omura, et. al., J. Antibiotics, 38, 1016 (2985); and M.Murata et. al T. Miyasaka, H. Tanaka, S. Omura, J. Antibiotics, 38, 1025(1985)]. However, Diazaquinomycine A is inactive as an antitumoralagent.

It has now been found, in accordance with the present invention, thatcertain azaanthracene-triones, as hereinafter defined, possessantitumoral activity.

SUMMARY OF THE INVENTION

According to the invention, therefore, there are provided azaanthracenetriones of the general formula: ##STR2## in which: R¹, R², R⁴ and R⁵ arethe same or are different and each is a hydrogen atom or a lower (C₁-C₆) alkyl group;

R³ is a hydrogen atom, a lower (C₁ -C₆) alkyl group, or a phenyl oramino-substituted phenyl group (preferably a dialkylamino substitutedphenyl group), at least one of R¹, R², R³, R⁴ and R⁵ being other thanhydrogen; and

X is a group --CH--, ═N-- or --NH-- whereby the ring containing thegroup X is a benzene, pyridine or dihydropyridene ring, respectively.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention also provides pharmaceutical compositions comprising acompound of formula (I) in association with a pharmaceutical carrier ordiluent. The invention further provides the use of a compound of formula(I) in the manufacture of an antitumoral composition. Finally, theinvention provides a method for the treatment of tumors using compoundsof formula (I).

The compounds of formula (I) may be subdivided into three sub-classes,namely:

(i) 5,8-dihydro-1H-1,8-diazaanthracene 2,9,10-triones of the formula:##STR3## (ii) 1H-1,8-diazaanthracene-2,9,10-triones of the formula:##STR4## (iii) 1H-1-azaanthracene-2,9,10-triones of the formula:##STR5##

The compounds of formulae (I) may be prepared by Diels-Alder addition ofan N,N-dimethylhydrazone of an appropriately substituted alkenal,followed by later treatment if necessary.

Thus, compounds of formulae I(a) and I(b) may be prepared by reaction ofa dimethylhydrazone of the formula: ##STR6## with an azanaphthoquinoneof the formula: ##STR7## in which case it has been found that reactionmay occur to give compounds of formula I(a) or I(b) depending on thenature of the dimethylhydrazone. Compounds of formula I(a) may beconverted to compounds of formula I(b) by oxidation.

Compounds of formula I(c) may be prepared by reaction of adimethylhydrazone of the formula: ##STR8## with a naphthaquinone of theformula: ##STR9## followed by conversion of the resultingazaanthraquinone to its N-oxide and subsequent conversion of this (byreaction with benzoyl chloride and water) to the desired trione.

The starting materials are known or may be prepared usingwell-established technique.

Thus, for example the dienophile, 4-methyl-(1H)-quinoline-2,5,8-trione,may be obtained by acetoacetylation of 2,5-dimethoxyaniline with2,2,6-trimethyl-4H-1,3-dioxin-4-one, followed by Knorr cyclization withsulfuric acid, demethylation with hydrobromic acid and oxidation withpotassium dichromate in an acidic medium. The starting dienophile,3-ethyl-1H-quinoline-2,5,8-trione, may be obtained throughVilsmeier-Haack formylation of 2,5-dimethoxybutyranilide, followed byacidic hydrolysis and oxidative demethylation with cerium ammoniumnitrate.

Diels-Alder reaction between these dienophiles andN,N-dimethylhydrazones (Helv. Chim Acta, 71, 486) of 2-butenal,2-methyl-2-pentenal, 3-phenyl-2-propenal, or3-(4-dimethylamino-phenyl)-2-propenal affords the partially oxidized3,8-dihydro adducts. The same reaction, when conducted ondimethylhydrazones of 2-methylpropenal and 2-ethylpropenal, givesaromatized adducts. In all cases, the Diels-Alder adducts areaccompanied by secondary products formed in the addition ofdimethylamine to the C₆ position of the starting quinone. The dihydroderivatives may be oxidized by air in refluxing xylene to thecorresponding aromatic compounds.

The Diels-Alder reaction of the N,N-dimethylhydrazone of2-methyl-2-propenal with naphthaquinone gives3-methyl-1-azaanthraquinone; this compound is then N-oxidized with H₂ O₂/F₃ C--CO₂ H, followed by treatment with benzoyl chloride and water togive the compound of formula I(c).

In order that the invention my be well understood the following Examplesare given by way of illustration only.

Melting points are uncorrected, and were determined in open capillarytubes, using a Buchi immersion apparatus. Combustion elemental analyseswere obtained using a Perkin Elmer 2400 CHN analyzer. Spectroscopic datawere obtained with the following instruments: IR, Perkin Elmer 577 andBuck Scientific 500; NMR, Varian VXR-300 (300 MHz for ¹ H and 75 MHz for¹³ C) and Bruker Ac-250 MHz for ¹ H and 63 MHz for ¹³ C). Theassignments indicated with * and ** can be interchanged.

EXAMPLE 1 Synthesis of4,6-dimethyl-5-5,8-dihydro-1H-1,8-diazaanthracene-2,9,10-trione (1)

To a solution of 4-methyl-1H-quinoline-2,5,8-trione (196) mg, 1 mmol) indry chloroform (130 ml) under nitrogen was added 159 mg (1.14 mmol) of2-methyl-2-pentenal dimethylhydrazone. The solution was stirred at roomtemperature for 5 minutes. After evaporation of the solvent, the residuewas purified by column chromatography on silica gel, eluting withdichloromethane/ethyl acetate (6:4) to give 33 mg of unreactedhydrazone, 133 mg (45%) of 1 and 105 mg of6-dimethylamino-4-metlhyl-1H-quinoline-1,5,8-trione.

Melting point: 220°-223° C.

IR(KBr): 3640-3060 (N--H); 1650 (C═O) cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ 6.65 (m, 2H, C₃ --H and N₈ --H); 6.10 (dd,1H, J₇.8 =4.5 Hz and J=1.2 Hz, C₇ --H): 3.65 (t, 1H, J=4.5 Hz, C₅ --H);2.62 (d, 3H, J=1.2 Hz, C₄ --CH₃); 1.73 (d, 3H, J=1.2 Hz, C₆ --CH₃); 1.56(dq, 2H, J=7.5 and 4.5 Hz, C₅ --CH₂ --CH₃); 0.81 (t, 3H, J=7.5 Hz, C₅--CH₂ --CH₃) ppm.

¹³ C-NMR (75.4 MHz, CDCl₃) δ 183.08 (C₉); 175.79 (C₁₀); 160.83 (C₂);152.03 (C₄); 137.11 (C_(8a))*; 136.33 (C_(9a))*; 127.76 (C₃); 119.49(C₇); 115.46 (C₆); 114.93 (C_(4a)); 111.51 (C_(10a)); 36.43 (C₅); 25.46(C₅ --CH₂ --CH₃); 22.53 (C₄ --CH₃); 18.68 (C₆ --CH₃); 9.27 (C₅ --CH₂--CH₃) ppm.

EXAMPLE 2 Synthesis of4-methyl-5-phenyl-5,8-dihydro-1H-1,8-diazaanthracene-2,9,10-trione (2)

A solution of 233 mg (1.34 mmol) of trans-cinnamaldehydeN,N-dimethylhydrazone was added to a solution of4-methyl-1H-quinoline-2,5,8-trione (127 mg, 0.67 mmol) in dry chloroform(120 ml). The reaction was stirred under nitrogen at room temperaturefor 3 days, with periodical additions of solvent (100 ml each 12 h). Afurther amount of 166 mg (0.61 mmol) of the hydrazone was added, and thereaction was refluxed for 24 h and evaporated to dryness, and theresidue was purified by silica gel chromatography using a gradientelution, starting with neat dichloromethane to dichloromethane/ethylacetate (7:3), to yield 204 mg of the starting diene, 72 mg (35%) of 2and 160 mg of 6-dimethylamino-4-methyl-1H-quinoline-2,5,8-trione.

Melting point, 206° C.

IR (KBr): 3400 (NH), 1660, 1655, 1600 (C═O) cm⁻¹.

¹ H-NMR (300 MHz, d₅ -pyridine) δ: 10.40 (d, 1H, J=4.0 Hz, N8--H); 7.69(dd, 2H, J_(2'), 3' =8.0 Hz, J_(2'), 4' =1.0 Hz, C_(2') --H, C_(6')--H); 7.41 (t, 2H, J=8.0 Hz, C_(3') --H, C_(5') --H); 7.25 (tt, J_(4'),3' =7.8 Hz, J_(4'), 2' =1.1 Hz, C_(4') --H); 6.70 (m, 2H, C₃ --H, C₇--H); 5.17 (m, 1H, C₆ --H); 5.11 (d, 1H, J=5.0 Hz, C₅ --H), 2.46 (d, 3H,J=1.0 Hz, C₄ --CH₃) ppm.

EXAMPLE 3 Synthesis of 5-(4-Dimethylamino-phenyl)4-methyl-5,8-dihydro-1H-1,8-diazaanthracene-2,9,10-trione (3).

A solution of 41.5 mg (2.2 mmol) of 4-methyl-1H-quinoline-2,5,8-trionein dry chloroform (130 ml) and 524 mg (2.4 mmol) ofN,N-dimethylhydrazone of p-dimethylaminocinnamaldehyde was stirred underreflux during four days. After evaporation of the solvent, the residuewas purified by silica gel chromatography using gradient elution fromdichloromethane to dichloromethane/ethyl acetate (7:3), to yield 80 mg(11%) of 3 and 313 mg of6-dimethyl-amino-4-methyl-1H-quinoline-2,5,8-trione.

Melting point: 252°-256° C.

IR (KBr): 3630-3100 (NH), 1650, 1640, 1635 (C═O) cm⁻¹.

¹ H-NMR (300 MHz, d₅ -pyridine) δ 10.24 (d, 1H, J=3.0 Hz, N8--H); 7.62(d, 2H, J=8.8 Hz, C₂ '--H, C_(6') --H); 6.85 (d, 2H, J=8.8 Hz, C_(3')--H, C_(5') --H); 6.76 (m, C₇ --H); 6.74 (s, 1H, C₃ --H); 2.78 (s, 6H,N(CH₃)₂); 2.54 (s, 3H, C₄ --CH₃) ppm. (The signal of C₆ --H is includedin the water signal).

EXAMPLE 4 Synthesis of 4,5-dimethyl-1H-1,8-diazaanthracene-2,9,10-trione(4)

a) A solution of 1.45 mg (0.76 mmol) of4-methyl-1H-quinoline-2,5,8-trione in dry chloroform (130 ml) and 85 mg(0.76 mmol) of dimethylhydrazone of crotonaldehyde was stirred at roomtemperature for five minutes. After evaporation of the solvent, theresidue was purified by silica gel chromatography, using a gradientelution from dichloromethane to dichloromethane/ethyl acetate (6:4), toyield 100 mg (51%) of4,5-dimethyl-5,8-dihydro-1H-1,8-diazaanthracene-2,9,10-trione(4), 43 mgof the starting hydrazone and 62 mg of6-dimethylamino-4-methyl-1H-quinoline-2,5,8-trione.

Melting point: 301°-303° C.

IR (KBr): 3660-3040 (N--H); 1660, 1650 (C═O) cm⁻¹.

1N-NMR (300 MHz, d₆ -DMSO) δ: 8.77 (d, 1H, J=3.6 Hz, N₈ --H); 6.54 (d,1H, J--1.2 Hz, C₃ --H); 6.14 (dd, 1H, J₇,8 =4.0 Hz, J₇.6 =7.8 Hz, C₇--H); 4.85 (m, 1H, C₆ --H); 3.50 (m, 1H, C₅ --H); 2.55 (s, 3H, C₄--CH₃); 1.02 (d, 3H, J=3.6 Hz, C₅ --CH₃) ppm.

b) A solution of 80 mg (0.31 mmol) of4,5-dimethyl-5,8-dihydro-1H-1,8-diazaanthracene-2,9,19-trione in xylene(60 ml) was refluxed for 58 hours, while air was bubbled through it.After evaporation of the solvent the residue was purified by silica gelchromatography using ethyl acetate as eluent, to yield 75 mg (95%) of 4.

Melting point: 258°-261° C. (ethyl acetate)

IR (KBr): 3440 (NH); 1655 (C═O) cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ: 8.85 (d, 1H, J=5.1 Hz, C₇ --H); 7.53 (d, 1H,J=4.8 Hz, C₆ --H); 6.72 (d, 1H, J=1.2 Hz, C₃ --H); 2.86 (s, 3H, C₅--CH₃); 2.68 (d, 3H, J=1.2 Hz, C₄ --CH₃) ppm.

¹³ C-NMR (75.4 MHz, CDCl₃) δ 160.45 (_(8a)); 153.31 (C₇): 152.02 (C₅);151.58 (C₄ ; 147.21 (C_(9a) ; 132.81 (C₆ ; 129.26 (C_(10a)); 128.78(C₃); 119.24 (C_(4a)); 29.26 (C₅ --CH₃); 22.82 (C₄ --CH₃) ppm.

EXAMPLE 5 Synthesis of6-ethy-4-methyl-1H-1,8-diazaanthracene-2,9,10-trione (5)

A solution of 150 mg (0.9 mmol) of 4-methyl-1H-quinoline-2,5,8-trioneand 150 mg (0.79 mmol) of 2-ethylacrolein dimethylhydrazone in drychloroform (130 ml) was stirred at room temperature for five minutes.After evaporation of the solvent, the residue was purified by silica gelchromatography using ethyl acetate as eluent to yield 29 mg of thestarting hydrazone, 64 mg (30%) of 5 and 60 mg of6-dimethylamino-4-methyl-1H-quinoline-2,5,8-trone.

Melting point: 225°-227° C. (ethyl acetate).

IR (KBr): 3420 (N--H); 1656, 1636 (C═O) cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃): δ 9.78 (bs, 1H, N--H); 8.90 (s, 1H); 2.89 (q,2H, J=9.1 Hz, C₆ --CH₂ --CH₃): 2.71 (s, 3H, C₄ --CH₃ ; 1.38 (t, 3H,J=9.1 Hz, C₆ --CH₂ --CH₃) ppm.

₁₃ C-NMR (75 MHz, CDCl₃) δ: 180.93 (C₉); 176.30 (C₁₀ ; 171.19 (C₂);160.06 (C_(8a)); 154.89 (C₇); 151.78 (C₄); 146.47 (C₆); 140.14 (C_(9a));133.92 (C₅ ; 130.51 (C_(10a)); 128.07 (C₃); 115.16 (C_(4a)); 26.59 (CH₂--CH₃); 21.07 (C₄ --CH₃); 14.20 (CH₂ --CH₃) ppm.

EXAMPLE 6 Synthesis of5-(p-dimethylaminophenyl)-4-methyl-1H-1,8-diazaanthracene-2,9,10-trione(6)

A solution of 25 mg (0.07 mmol) of 3 in xylene (60 ml) was refluxed for16 hours while air was bubbling through the solution. After evaporationof the solvent, the residue was purified by silica gel chromatography,using ethyl acetate as eluent to yield 20 mg (80%) of 6.

Melting point: 305°-309° C. (ethyl acetate)

IR (KBr): 3650-3080 (N--H; 1676, 1664, 1656 (C═O) cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ 8.88 (d, 1H, J=4.8 Hz, C₇ --H); 7.56 (d, 1H,J=4.8 Hz, C₆ --H); 7.22 (d, 2H, J=8.8 Hz, C_(2') H and C₆ '--H); 6.77(d, 2H, J=8.6 Hz, C_(3') --H and C_(5') --H); 6.70 (d, 1H, J=1.2 Hz, C₃--H); 3.06 (s, 6H, N(CH₃)₂); 2.56 (d, 3H, J=1.2 Hz, C₄ --CH₃) ppm.

₁₃ C-NMR (63, Mhz, CDCl₃) δ 182.21 (C₉); 177.14 (C₁₀); 167.94 (C₂);160.39 (C_(8a)); 152.90 (C₇); 151.68 (C₅); 150.89 (C₄); 147.59 (C_(4'));132.58 (C_(6*)); 131.06 (C_(1'*)); 129.56 (C_(2') and C_(6')); 128.96(C_(3**)); 128.58 (C_(10a**)); 117.51 (C_(4a)); 111.84 (C_(3') andC_(5')); 40.35 (N(CH₃)2); 22.56 (C₄ --CH₃) ppm.

EXAMPLE 7 Synthesis of3-ethyl-6-methyl-1H-1,8-diazaanthracene-2,9,10-trione (7)

a) To a cooled solution of 2,5-dimethoxyaniline (1 g, 0.65 mmol) in drybenzene (7 ml). The reaction was stirred at room temperature for 1 h andwas then quenched with cold 25% aqueous sodium carbonate (10 ml). Aftervigorously stirring the two-phase system for 30 min, the benzene layerwas separated and the aqueous phase was extracted with ethyl ether (3×50ml). The combined organic layers were dried over sodium sulphate andevaporated, and the residue (7) was crystallized from petroleum ether,Yield, 86%.

Melting point: 34° C. (petroleum ether)

Ir (KBr): 3235 (NH); 1660(C═O); 1235 (OCH₃) cm⁻¹.

¹ H-NMR (300 MHzm, CDCl₃) δ: 8.10 (d, 1H, J=3.0 Hz, C_(6') --H); 7.80(s, 1H, NH); 6.70 (d, IH, J=7.5 Hz, C_(3') --H); 6.50 (dd, 1H, J=7.5 and3.0 Hz, C_(4') --H); 3.80 (s, 3H, C_(5') --OCH₃); 3.70 (s, 3H, C_(2'--)OCH₃); 2.40 (c, 3H, J=7.5 Hz, C₂ --H); 1.20 (t, 3H, J=7.5 Hz, C₃ --H)ppm.

¹³ C-NMR (75.4 MHz, CDCl₃) δ: 171/87 (C₁); 153.80 (C_(5')); 141.77(C_(2')); 128.34 (C_(1')); 110.55 (C_(3')); 108.34 (C_(4')); 105.64(C_(6')); 56.10 and 55.68 (2 OCH₃); 30.98 (C₂); 9.55 (C₃) ppm.

b) A mixture of phosphorus oxychloride (3 ml, 31.6 mmol) anddimethylformamide (0.52 ml, 6.6 mmol) was stirred at -30° C. for 15 min,while kept in a nitrogen atmosphere. 1 g (4.5 mmol) ofN-(2,5-dimethoxyphenyl)butanamide was then added in one portion, and thesolution was heated for two hours at 110° C. On completion of thereaction, as monitored by tlc, the solution was poured on crused ice,basified with 25% aqueous ammonium hydroxide and extracted withchloroform (3×50 ml). The organic layers were dried over sodium sulphateand evaporated, and the residue was purified by silica gelchromatography using petroleum ether/ethyl ether (2:1) as eluant, togive 856 mg (75%) of 2-chloro-3-ethyl-5,8-dimethoxyquinoline.

Melting point, 120° C. (ethyl ether-petroleum ether).

Ir (Kbr): 1265 (OCH3) cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ: 8.35 (s, 1H, J=8.0 Hz, C₇ --H); 6.74 (d, 1H,J=8.0 Hz, C₆ --H); 4.01 (s, 3H, C₈ --OCH₃); 3.95 (s, 3H, C₅ --OCH₃);2.92 (c, 2H, J=7.5 Hz, CH₂ --CH₃); 1.30 (t, 3H, J=7.5 Hz, CH₂ --CH₃)ppm.

¹³ C-NMR (75.4 MHz, CDCl₃) δ: 151.34 (C₂); 148.39 (C_(5*)); 148,08(C_(8*)); 138.29 (C_(8a)); 135.30 (C₃); 131.43 (C₄); 120.84 (C_(4a));106.99 (C₇); 103.97 (C₆); 55.65 and 55.91 (2 OCH₃); 26.52 (CH₂ --CH₃);13.44 (CH₂ --CH₃) ppm.

c) A solution of 200 mg (0.92 mmol) of2-chloro-3-ethyl-5,8-dimethoxyquinoline in acetic acid (3 ml) and water(1 ml) was refluxed for 5 h. After evaporation of the solvent, theresidue was dissolved in water, basified with 25% aqueous ammoniumhydroxide and extracted with chloroform (3×25 ml). The combinedchloroform layers were dried over sodium sulphate and evaporated,yielding 185 mg (100%) of 3-ethyl-5,8-dimethoxy-1H-quinolin-2-one.

Melting point, 160° C. (ethanol).

1R (KBr): 3240-2810 (NH); 1650 (C₂ ═O); 1245 (2 OCH₃) cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ: 9.18 (s, 1H, C₄ --H); 6.78 (d, 1H, J=8.7 Hz,C₇ --H); 6.46 (d, 1H, J=8.7 Hz, C₆ --H); 3.88 and 3.87 (2s, 6H 2 OCH₃);2/56 (c, 2H, J=9.0 Hz, CH₂ --CH₃); 1.25 (3H, J=9.0 Hz, CH₂ --CH₃) ppm.

¹³ C-NMR (63 MHz, CDCl₃) δ: 162.10 (C²); 149.25 (C₅); 139.45 (C₈);135.11 (C_(8a)); 129.83 (C₄); 128.19 (C₃ ; 111.14 (C_(4a)); 108.94 (C₇);100.95 (C₆); 56.08 and 55.67 (2 OCH₃); 23.45 (CH₂ --CH₃); 12.64 (CH₂--CH₃) ppm.

d) Cerium ammonium nitrate (284 mg, 0.5 mmol) was added in smallportions to a stirred suspension of3-ethyl-5,8-dimethoxy-1H-quinolin-2-one(50 mg, 0.2 mmol) in water (0.5ml) and acetonitrile (1 ml). After 5 minutes at room temperature, water(3 ml) was added and the reaction mixture was extracted with chloroform(3×20 ml), yielding 3-ethyl-1H-quinoline-2,5,8-trione (44 mg, 100 %).The analytical sample was obtained by rapid silica gel chromatography,eluting with ethyl ether.

Melting point 168° C.

IR (KBr): 1650 (C═O) cm.

¹ H-NMR (300 MHz, CDCl₃) δ: 9.60 (s, 1H, NH); 7.75 (s, 1H, C₄ --H); 6.87(m, 2H, C₇ --H and C₆ --H); 2.66 (c, 2H, J=7.8 Hz, CH₂ --CH₃); 1.26 (t,3H, J=7.8 Hz, H₂ --CH₃) ppm.

¹³ C-NMR (75.4 MHz, CDCl₃) δ: 177.92 (cg); 174.79 (C₅); 156.81 (C₂);138.98 (C_(8a)); 133.50 (C₆); 130.57 (C₃); 129.96 (C₇); 125.33 (C₄);110.39 (C_(4a)); 19.17 (CH₂ --CH₃); 7.33 (CH₂ --CH₃) ppm.

e) A suspension of 3-ethyl-1H-quinoline-2,5,8-trione (200 mg, 0.99 mmol)in chloroform (40 ml) is treated with 145 mg (1.3 mmol) of2-methylpropenal dimethylhydrazone. The reaction was stirred at roomtemperature for 5 minutes and evaporated, and the residue waschromatographed on silica gel, eluting with ethyl acetate, to yield 120mg (45%) of 7.

Melting point, 260°-262° C.

¹ H-NMR (250 MHz, CDCl₃) δ: 9.70 (br. s, 1H, NH) 8.95 (s, 1H, C₇ --H);8.35 (s, 1H, C₅ --H); 7.96 (s, 1H, C₄ --H); 2.63 (q, 2H, J=7.5 Hz, CH₂--CH₃); 2.60 (s, 3H, C₆ --CH₃); 1.30 (t, 3H, J=7.5 Hz, CH₂ --CH₃) ppm.

¹³ C-NMR (63 MHz, CDCl₃) δ: 179.91 (C₉): 176.20 (C¹⁰); 171.10 (C₂);161.37 (C_(8a)); 155.36 (C₇); 144.52 (C₃); 140.16 (C₆); 137.25 (C_(9a));134.94 (C₅); 130.30 (C₄ and C_(10a)); 129.35 (C₃); 116.26 (C_(4a));23.93 (C₆ --CH₃); 12.01 (C₃ --CH₂ --CH₃) ppm.

EXAMPLE 8 Synthesis of 3-Methyl-1H-1azaanthracene-2,9,10-trione (8)

a) A solution of 30-methyl-1-azaanthraquinone (1 g, 4 mmol) intrifluoroacetic acid (6 ml) was treated with percarbamide (0.63 g) andstirred at room temperature for 24 h, with hourly additions of 315 mg ofpercarbamide up to a total amount of 1.58. The solution was stirred for24 hours. The addition of ethyl acetate (6 ml) gave an orange solidwhich was washed with water to afford 0.89 g (83%) of3-methyl-1-azaanthracenequinone-1-oxide. Crystallization from ethylacetate/ethanol (9:1) yielded 0.54 of orange needles.

Melting point could not be obtained, as the N-oxide decomposed onheating.

IR (KBr): 1680 (O--O) cm⁻¹.

¹ H-NMR (250 MHz, CDCl₃) δ: 8.41 (s, 1H, C₂ --H); 8.37 (dd, 1H, J₅₋₆=1.21 Hz, C₅ --H); 8.24 (dd 1H, J₈₋₇ =7.3 Hz, J₈₋₆ =1.71 Hz, C₈ --H);7.95 (s, 1H, C₄ --H); 7.84 (m, 2H, C₆ --H and C₇ --H); 2.46 (s, 3H, CH₃)ppm.

b) To a solution of the N-oxide (125 mg, 0.523 mmol) inamylene-stabilized chloroform (12 ml) were added three portions of 0.1ml (2.5 mmol) of benzoyl chloride in 1/2 hour intervals. The solutionwas stirred at 60° C. for 3 h, and was then treated with water (0.4 ml)and kept at 60° C. for 1 h and for further 12 h at room temperature. Theprecipitated yellow solid was filtered and washed with ethyl ether andpetroleum ether, yielding 80 mg (64%) of 8.

Melting point>300° C.

IR (KBr): 3640-3300 (NH); 1680, 1670, 1640 (C═O) cm⁻¹.

¹ H-NMR (300 MHz, CDCl₃) δ: 8.25 (dd, 1H, J₇₋₈ =7.3, J₈₋₆ =1.47 Hz, C₈--H); 8.20 (dd, 1H, J₅₋₆ =7.3 Hz, J₅₋₇ =1.47 Hz, C₅ --H); 8.00 (q, 1H,J=1.20 Hz, C₄ --H); 7.82 (m, 1H, C₆ --H and C₇ --H); 2.31 (d, 3H, J=1.20Hz, CH₃) ppm.

BIOLOGICAL ACTIVITY

Compounds were diluted in DMSO/MeOH/Acetone (1:4.5:4.5) and they weretested at different concentrations. The solvent was allowed to evaporatebefore the cells were seeded.

The following antitumoral assay, employing the current screeningprotocol has been carried out using the following cell line:

P-388 (lymphoid neoplasm from DBA/2 mouse).

Assay Against P-388 Cells (Lymphoidneoplasm from DBA/2 Mouse )

P-388 cells were seeded into 16 mm wells at 1×10⁴ cells per well in 1 mlaliquots of MEM 10C containing different concentrations of the compound.All determinations were carried out in triplicate. A separate set ofcultures without drug was counted daily to ensure that the cellsremained in exponential growth over the period of observation. Afterthree days of incubation, cells were counted and the IC₅₀ wasdetermined.

    ______________________________________                                        COMPOUNDS       IC.sub.50 μg/ml                                            ______________________________________                                        1               1                                                             2               0.25                                                          3               20                                                            4               1                                                             5               0.5                                                           6               1                                                             7               0.2                                                           8               0.2                                                           ______________________________________                                    

What is claimed is:
 1. The diazaquinomicin analog represented by thefollowing structure: ##STR10##
 2. An antiumoral pharmaceuticalcomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable carrier or diluent.
 3. A method of inhibiting the growth ofmammalian tumor cells comprising administering to said mammalian cellsan effective growth inhibiting amount of the compound of claim 1, andwherein said tumor cells are lymphoid neoplasm cells.